18-12986891-G-T

Variant names:

• chr18-12986891-G-T
• rs372017827
• NM_001013437.2:c.1100G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001013437.2(SEH1L):​c.1100G>T​(p.Arg367Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,455,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R367P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SEH1L NM_001013437.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.77
• Publications: 0 publications found

Genes affected

SEH1L (HGNC:30379): (SEH1 like nucleoporin) The protein encoded by this gene is part of a nuclear pore complex, Nup107-160. This protein contains WD repeats and shares 34% amino acid identity with yeast Seh1 and 30% identity with yeast Sec13. All constituents of the Nup107-160 complex, including this protein, specifically localize to kinetochores in mitosis. Two alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

CEP192-DT (HGNC:55313): (CEP192 divergent transcript)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19347453).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001013437.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEH1L	NM_001013437.2	MANE Select	c.1100G>T	p.Arg367Leu	missense	Exon 9 of 9	NP_001013455.1	Q96EE3-1
	SEH1L	NM_031216.4		c.*1639G>T		3_prime_UTR	Exon 9 of 9	NP_112493.2	Q96EE3-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEH1L	ENST00000399892.7	TSL:1 MANE Select	c.1100G>T	p.Arg367Leu	missense	Exon 9 of 9	ENSP00000382779.1	Q96EE3-1
	SEH1L	ENST00000262124.15	TSL:1	c.*1639G>T		3_prime_UTR	Exon 9 of 9	ENSP00000262124.10	Q96EE3-2
	SEH1L	ENST00000590843.1	TSL:1	n.4566G>T		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455106 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 724088

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33140

American (AMR) AF: 0.00 AC: 0 AN: 44342

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25902

East Asian (EAS) AF: 0.00 AC: 0 AN: 39358

South Asian (SAS) AF: 0.00 AC: 0 AN: 85740

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53156

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5732

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107726

Other (OTH) AF: 0.00 AC: 0 AN: 60010

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	17
DANN	Uncertain	0.98
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.63
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.0	T
PhyloP100		3.8
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.10
Sift	Uncertain	0.010	D
Sift4G	Benign	0.32	T
Polyphen		0.0	B
Vest4		0.53
MutPred		0.27		Loss of MoRF binding (P = 0.0589)
MVP		0.36
MPC		0.50
ClinPred		0.90	D
GERP RS		0.063
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
gMVP		0.65
Mutation Taster		=72/28	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs372017827; hg19: chr18-12986890;